Microdialysis is a technique used to monitor the chemistry of the extracellular or interstitial space in biological tissue. For many years, the use of microdialysis sampling in research and therapeutics has proven to have many advantages, such as clean samples, more frequent samples, and conservation of body fluid. In addition, microdialysis provides a direct profile of substances within tissues of interest, whereas many conventional methods depend upon calculating the tissue concentration indirectly from serial blood samples. Therefore, microdialysis provides a preview of chemical changes in the tissue before those events are reflected as chemical changes in the blood.
A microdialysis probe is a device that is introduced into tissue and is designed to mimic a blood capillary in function. When a physiological salt solution, called the perfusion fluid or dialysis medium (e.g., Ringer solution), is slowly perfused through the microdialysis probe, it draws chemical substances from the extracellular space into the probe as it equilibrates with the extracellular fluid such that the probe will eventually contain a representative proportion of molecules found in the extracellular space. Therefore, the microdialysis technique allows the investigation of discrete local tissue function directly at the cellular level and is well suited for diagnostic applications involving metabolism, endocrinology, toxicology, pharmacokinetics, neurotransmission, and other studies.
Various designs of microdialysis probes have been developed for particular sites or types of tissues. For example, microdialysis probes can be flexible or rigid, and the in and out flow paths can be looped, side-by-side, or concentric, as described in U.S. Pat. No. 5,191,900. In a concentric probe design, the perfusion medium typically enters the probe through an inner tube and is pumped slowly to the distal end of the inner tube where it flows into the tip of the probe, which is surrounded by the dialysis membrane. This is the site of dialysis, i.e., diffusion of substances across and back from the extracellular fluid. The resulting dialysate exits the probe by flowing through a larger outer tube, where it is collected for analysis.
Dialysis is bi-directional in that there is exchange of molecules in both directions across the membrane. The difference in the concentration of a specific molecule across the dialysis membrane will determine the direction of the diffusion gradient. As a result of this property, the microdialysis technique not only allows measurement and quantification of endogenous molecules, the technique can also be used for site-specific drug delivery to the extracellular space (Rongquist, G. et al. [1992] Treatment of Malignant Glioma by a New Therapeutic Principle” Acta Neurochir 114:8-11; Muller, M. et al. [1997] In vivo Drug Response Measurements in Target Tissues by Microdialysis” Clin Pharmacol Ther 62:165-170). For example, one can collect an endogenous substance, such as neurotransmitter, and at the same time introduce an exogenous substance, such as a receptor agonist or antagonist, into the extracellular space.
The microdialysis technique has become more popular in recent years and a number of significant advances have been made. The use in clinical and research applications on humans has been slow, however, primarily because microdialysis probes are naturally fragile, which makes them difficult to insert. At least one part of the probe must have a surface that is composed of the thin, semi-permeable dialysis membrane, which is easily broken.
Many microdialysis probes are introduced into tissue by first inserting a metal needle into the lumen of a plastic insertion cannula (also referred to as a guide cannula), such that the pointed tip of the needle extends beyond the distal end of the insertion cannula. The needle and cannula are then inserted into the tissue, with the needle tip piercing the tissue. The needle is then slid from the lumen of the insertion cannula, leaving only the insertion cannula in the tissue. A microdialysis probe is then inserted into the lumen of the insertion cannula so that the membrane at the distal end of the probe extends just beyond the distal end of the insertion cannula, into the tissue, where the needle tip had previously extended. Therefore, the insertion cannula permits insertion of the probe with minimal damage to the tissue beyond that caused by the needle.
Alternatively, the insertion cannula can itself define a pointed cutting edge at its distal end, eliminating the necessity of inserting a needle through the cannula and into the tissue. The microdialysis probe is then inserted into the lumen of the pointed insertion cannula. However, this arrangement is more traumatic and the lumen of the insertion cannula can become fouled with tissue upon insertion.
A conventional microdialysis probe usually includes at its proximal end a connecting part for connection to an ingoing and an outgoing hose or tubing. Because this connecting part typically has a larger outer diameter than the inner diameter of the insertion cannula, the insertion cannula cannot simply be slid over the connecting part. Some connecting parts also have one or more hoses that extend perpendicularly to the longitudinal axis of the probe, which also prevents easy removal of the insertion cannula. Therefore, the insertion cannula must remain in the tissue at the insertion site and cannot be removed until the probe is removed. Microdialysis probes of this type are described in U.S. Pat. Nos. 4,694,832 and 5,106,365. In some microdialysis probes with which the insertion cannula is left in situ, the probes further include an anchoring member at their distal end, which engages (e.g., screws into) the end of the insertion cannula, indirectly attaching the probe to the outside of the subject's body. Examples of such probes are described in U.S. Pat. No. 5,607,390.
These conventional probes have inherent problems when inserted into deeper tissues, such as organs. For example, when inserting a microdialysis probe into a lung, it is first necessary to make a surgical incision in the skin and the underlying chest wall. Due to the presence of the insertion cannula and any laterally projecting parts (e.g., connecting parts, anchoring member), the incision must be left open during sampling and/or drug delivery. This situation increases expense, as well as the risk of surgical complications, such as infection. In addition, because the insertion cannula and connecting part are often rigid, their presence can cause trauma to moving tissues (e.g., lung, muscle) that come in contact with these devices.
In an alternative design, the probe is inserted through a cannula tube (i.e., insertion cannula) and the cannula tube has a longitudinal slot, as described in U.S. Pat. No. 5,741,284. After the cannula tube is inserted into the tissue and the probe is inserted into the cannula tube, the cannula tube can be withdrawn because the probe can pass through the longitudinal slot of the cannula tube. The microdialysis probe also has a laterally extending wing mounted on its proximal end. The wing is held firmly during removal of the cannula tube so that the probe is not withdrawn from the tissue along with the cannula tube. After the cannula tube has been withdrawn and discarded, the wing is folded down against the skin and secured thereto with adhesive tape. While this arrangement may be used for insertion of the probe through the skin and soft underlying tissues, it would be less practical to insert this probe into deeper tissues, such as organs, which may necessitate a surgical incision through the chest wall. Due to the presence of the wing, the incision would have to be left open during sampling and/or drug delivery.
Alternatively, the insertion cannula can be designed to be “rupturable”. Such cannulas are also described in U.S. Pat. No. 5,607,390. A rupturable insertion cannula is typically constructed with longitudinal weakenings (e.g., perforations) such that the cannula can be pulled apart into two or more pieces and eliminated, leaving only the microdialysis probe positioned within the tissue. Hence, the rupturable insertion cannula is sometimes referred to as “split plastic tubing” or a “split introducer”. While this arrangement permits insertion of the microdialysis probe and removal of the insertion cannula, the methods involved are relatively troublesome and require the use of two or more hands for maneuvering and splitting apart the insertion cannula, and for preventing the microdialysis probe from accompanying the pieces of the insertion cannula as they are removed. In addition, the possibility exists for pieces of the insertion cannula to be unintentionally left behind within the tissue. This is particularly dangerous where an incision has been made in order to insert the probe into an organ or other deep tissue, because the presence of debris within the body can cause harm to the subject, such as infection and/or internal bleeding.
Another problem associated with microdialysis of deeper tissues is the inability to accurately target specific tissue layers. Some microdialysis probes are at least partially constructed of materials that could theoretically be detected and imaged within biological tissue using the appropriate imaging equipment, such as x-ray, ultrasound, magnetic resonance imaging (MRI), and the like. For example, probes that are at least partially ultrasound-visible have been used to study transdermal penetration of a drug in superficial tissues. The appropriate position of the microdialysis probe is established by two-dimensional ultrasound and the distance between the skin surface and the tip of the microdialysis probe are measured (Muller, M. et al. [2000] “Microdialysis in Clinical Drug Delivery Studies” Adv Drug Deliv Rev 45(2-3):255-269). However, the mechanical designs of these probes do not permit highly accurate placement of the “active” portion of the probe, i.e., the dialysis membrane, within the target tissue.
Therefore, there is a need for a microdialysis probe design that permits the insertion of the probe into tissue, particularly deeper tissues, without the disadvantages associated with conventional microdialysis probe designs.